Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB52FZ4)

• DOT Name: HEAT repeat-containing protein 3 (HEATR3)
• Gene Name: HEATR3
• Related Disease:
  Central nervous system neoplasm
  Crohn disease
  Diamond-Blackfan anemia 21
  Ewing sarcoma
  Glioblastoma multiforme
  Glioma
  Neoplasm
  Recessive X-linked ichthyosis
  Synovial sarcoma
  Liposarcoma
  Fibrosarcoma
  Neoplasm of esophagus
  Squamous cell carcinoma
• UniProt ID: HEAT3_HUMAN
• Pfam ID: PF13513
• Sequence:
  MGKSRTKRFKRPQFSPTGDCQAEAAAAANGTGGEEDDGPAAELLEKLQHPSAEVRECACA
  GLARLVQQRPALPGLARRDAVRRLGPLLLDPSLAVRETAAGALRNLSACGGFEVCDDMVT
  KDIMTPLVALLKECSAGLDSNEMSLQEKKDQNRNSIENIANETVNVLWNICECSSRAVSI
  FNKEGCLEIVLKYLSRFPTNVDLAISVAYCLQTVTEDNPELLKSFSATALNMLESALLSP
  VSSMESLLLKTLVAGTIWNLKDIIPCKSQAEIINALLKILSEVLGMDAGEMVIQMKEAET
  QRLKTAAEAEEILENTNGDDLIEDDEMEGISHKRRVRRKTFVSDLLPPTDKELRETIALL
  TAQQTALEIIVNMCCNEDPSDDEWEELSSSDESDAFMENSFSECGGQLFSPLCLSHEVHT
  ALTNYLIPKKIFEKTAFPNSIAVDLCSRNPTWKPLIRKMNTIQCRALFCLQSLVSLLDVE
  HLGGAAALQTLAQHLSQLLFSQPDFAKHVDFLEAISSALRALLQTMASKNISQCMTPDQL
  MTLCKAGIHSSNVGVRVNVVSILGITGSVLAKEDGTLETLKNIGCFLLEVTTKDPSLVVA
  GEALDALFDVFADGKEAERASIQIKLLSALKEFQPVFKMKIRKEGRGNYSTDQLCVLDNV
  KMNLRRFIAYQETVEKRLTS
• Function: Plays a role in ribosome biogenesis and in nuclear import of the 60S ribosomal protein L5/large ribosomal subunit protein uL18 (RPL5). Required for proper erythrocyte maturation.

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Central nervous system neoplasm	DISFC18W	Strong	Genetic Variation	[1]
Crohn disease	DIS2C5Q8	Strong	Genetic Variation	[2]
Diamond-Blackfan anemia 21	DISNNXA4	Strong	Autosomal recessive	[3]
Ewing sarcoma	DISQYLV3	Strong	Biomarker	[4]
Glioblastoma multiforme	DISK8246	Strong	Genetic Variation	[1]
Glioma	DIS5RPEH	Strong	Genetic Variation	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Recessive X-linked ichthyosis	DISZY56W	Strong	Biomarker	[6]
Synovial sarcoma	DISEZJS7	Strong	Genetic Variation	[5]
Liposarcoma	DIS8IZVM	moderate	Biomarker	[6]
Fibrosarcoma	DISWX7MU	Limited	Biomarker	[5]
Neoplasm of esophagus	DISOLKAQ	Limited	Genetic Variation	[7]
Squamous cell carcinoma	DISQVIFL	Limited	Genetic Variation	[7]

14 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of HEAT repeat-containing protein 3 (HEATR3).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of HEAT repeat-containing protein 3 (HEATR3).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of HEAT repeat-containing protein 3 (HEATR3).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of HEAT repeat-containing protein 3 (HEATR3).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of HEAT repeat-containing protein 3 (HEATR3).	[12]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of HEAT repeat-containing protein 3 (HEATR3).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of HEAT repeat-containing protein 3 (HEATR3).	[14]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of HEAT repeat-containing protein 3 (HEATR3).	[15]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of HEAT repeat-containing protein 3 (HEATR3).	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of HEAT repeat-containing protein 3 (HEATR3).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of HEAT repeat-containing protein 3 (HEATR3).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of HEAT repeat-containing protein 3 (HEATR3).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of HEAT repeat-containing protein 3 (HEATR3).	[21]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of HEAT repeat-containing protein 3 (HEATR3).	[15]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of HEAT repeat-containing protein 3 (HEATR3).	[20]

References

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• [2] Extended haplotype association study in Crohn's disease identifies a novel, Ashkenazi Jewish-specific missense mutation in the NF-B pathway gene, HEATR3.Genes Immun. 2013 Jul-Aug;14(5):310-6. doi: 10.1038/gene.2013.19. Epub 2013 Apr 25.
• [3] HEATR3 variants impair nuclear import of uL18 (RPL5) and drive Diamond-Blackfan anemia. Blood. 2022 May 26;139(21):3111-3126. doi: 10.1182/blood.2021011846.
• [4] Antitumor profile of the PI3K inhibitor ZSTK474 in human sarcoma cell lines.Oncotarget. 2018 Oct 12;9(80):35141-35161. doi: 10.18632/oncotarget.26216. eCollection 2018 Oct 12.
• [5] Glycogen synthase kinase 3 as a potential therapeutic target in synovial sarcoma and fibrosarcoma.Cancer Sci. 2020 Feb;111(2):429-440. doi: 10.1111/cas.14271. Epub 2019 Dec 30.
• [6] Curcumin and Viscum album Extract Decrease Proliferation and Cell Viability of Soft-Tissue Sarcoma Cells: An In Vitro Analysis of Eight Cell Lines Using Real-Time Monitoring and Colorimetric Assays.Nutr Cancer. 2017 Feb-Mar;69(2):340-351. doi: 10.1080/01635581.2017.1263349. Epub 2017 Jan 3.
• [7] Genome-wide association analyses of esophageal squamous cell carcinoma in Chinese identify multiple susceptibility loci and gene-environment interactions.Nat Genet. 2012 Oct;44(10):1090-7. doi: 10.1038/ng.2411. Epub 2012 Sep 9.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [10] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [14] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [15] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [16] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [19] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [20] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.